ABSTRACT The objective of this project is to develop, validate, and translate novel 18F-labeled PET (positron emission tomography) imaging ligands for synaptic vesicle glycoprotein 2A (SV2A). Such imaging probes are potentially useful for the early detection of Alzheimer?s disease (AD) through reliable in vivo quantification of synaptic density. AD is the most common neurodegenerative disease affecting more than 5 million Americans. AD patients lose their memory and cognitive capacity progressively along a continuum of preclinical stage, prodromal mild cognitive impairment (MCI), and AD dementia. Although the exact pathogenesis of AD is yet to be fully understood, and there is currently no cure for the disease, early detection of AD for better intervention outcomes has become a consensus in AD research community. While the imaging of pathological biomarkers, such as amyloid-? plaques and hyperphosphorylated tau tangles, have been extensively studied to detect prodromal AD, the most consistent biomarker of early AD, regional synaptic loss, has been less studied due to the lack of a suitable PET imaging probe. Because the extent of synaptic loss is a stronger correlate of cognitive decline than plaques, tangles, and neuronal loss, synaptic density imaging will allow longitudinal assessment of AD progression, and open a window for early intervention before the onset of devastating symptoms. Through our pilot PET imaging study using our lead SV2A ligand, 11C-UCB-J, we found significant synaptic loss in the hippocampus and frontal cortex of patients with MCI and AD. This decrease is more severe in AD (60% decrease) than MCI (30% decrease), indicating progressive synaptic loss along the disease progression pathway, which is consistent with findings in postmortem studies. These preliminary data demonstrate the feasibility and clinical potential of detecting preclinical and prodromal AD by SV2A PET imaging. Therefore, we propose to develop and translate an 18F-labeled SV2A PET imaging probe for multicenter clinical trials. The specific aims are: 1) To synthesize a library of SV2A-binding ligands containing fluorine at a position that can be readily radiolabeled, and evaluate their in vitro binding properties; 2) To radiofluorinate 3-5 of the most promising ligands for PET imaging evaluation of their in vivo properties, and to select the best ligand for translation to humans; 3) To correlate SV2A expression with the number of synapses using postmortem brain tissue of patients with MCI/AD and cognitively intact controls. Successful completion of this project will yield a PET tracer ready to be tested in multicenter clinical trials as a specific, sensitive, reliable, and quantitative biomarker for early detection of AD. Early detection of AD by SV2A PET will allow early interventions to slow or halt disease progression. It will also allow the non-invasive longitudinal tracking of AD progression and objective assessment of therapeutic effects in clinical trials of disease-modifying interventions. Further, as synaptic dysfunction is indicated in other neurological disorders, ex., autism, Parkinson?s disease, epilepsy, and traumatic brain injury, SV2A PET imaging can also find wide applications in the investigation and monitoring of these diseases.